A Formal Intermolecular Iodolactonization Reaction Based on a Radical-Ionic Sequence

Article abstract of DOI:10.1002/ejoc.201600051

We report herein a method based on a radical-ionic sequence between an allylic alcohol and an α-iodo acid in the presence of substoichiometric amounts of lauroyl peroxide (DLP) to produce an atom transfer radical addition (ATRA) adduct, which subseqently

Full text of DOI:10.1002/ejoc.201600051

DOI: 10.1002/ejoc.201600051
Full Paper
Synthetic Methods
A Formal Intermolecular Iodolactonization Reaction Based on a
Radical-Ionic Sequence
David F. León-Rayo,[a] Maricela Morales-Chamorro,[a] and Alejandro Cordero-Vargas*[a]
Abstract: We report herein a method based on a radical-ionic followed by an intermolecular iodolactonization. Twenty-two
sequence between an allylic alcohol and an α-iodo acid in the experiments were carried out to evaluate the scope of the reac-
presence of substoichiometric amounts of lauroyl peroxide tion, which afforded a wide variety of iodo lactones with diverse
(DLP) to produce an atom transfer radical addition (ATRA) ad- functionalities. The utility of this approach was demonstrated
duct, which subseqently underwent an acid-mediated lactoni- in the synthesis of the natural product (–)-de-O-methylcentro-
zation. This approach can be described as a free radical reaction lobine.
Introduction
Since Boughoult's[1] discovery in 1904, the halolactonization re-
action has received much attention and has become a current
strategy for retrosynthetic analysis. The transformation involves
the conversion of ꢀ,γ- and γ,δ-unsaturated carboxylic acids 1
and 3 into the corresponding five- or six-membered lactones
that contain a halogen atom at the ꢀ-, γ-, or δ-position (i.e., 2,
4, and 5; Scheme 1).[2] The compounds obtained by this
method are valuable synthetic intermediates, as both carbonyl
and halogen groups can be further functionalized.[3] The halo-
lactonization of γ,δ-unsaturated carboxylic acid 3 is of special
Scheme 1. Typical intramolecular halolactonizations.
interest, because it allows for the possibility of preparing either
γ- or δ-lactones. Both the regio-[3] and stereoselectivity[4] of the
process depend on the ionic nature of the reaction, the Baldwin
rules, and the reaction conditions. In fact, γ,δ-unsaturated carb-
oxylic acid 3 typically affords the corresponding γ-lactone 5
unless special structural elements are used to control the regio-
selectivity of the transformation (i.e., R1 = aryl group). To the
best of our knowledge, halo- and selenolactonization reactions
are intramolecular processes, which can present a challenge
with regard to the preparation of the required unsaturated
carboxylic acid.
However, atom transfer radical additions[5] (ATRAs or Kharash
reactions) are powerful tools for the simultaneous construction
of carbon–carbon and carbon–heteroatom bonds and produce
valuable synthetic intermediates that are embedded with vari-
ous functional groups for further synthetic manipulation. Re-
cently, our group reported some new radical-ionic sequences
for the synthesis of epoxides[6] and 1,4-dicarbonyl com-
pounds[7] by employing an initial ATRA reaction, in which the
adduct is not isolated but treated under ionic conditions (basic
media or silica gel) to afford the desired molecular skeleton. On
the basis of the above results, we propose that the application
of an ATRA reaction between α-iodo acid or α-iodo ester 6 and
allylic alcohol 7 would yield adduct 8, which could be trans-
formed into lactone 9 under standard conditions. Thus, the
overall transformation might be rationalized as a formal inter-
molecular iodolactonization reaction (Scheme 2). This strategy
would exclusively produce γ-iodo-δ-lactones regardless on the
[a] Instituto de Química, Universidad Nacional Autónoma de México,
Circuito exterior s/n, Ciudad Universitaria, Coyoacán, 04510, México, D.F.,
México
E-mail: acordero@unam.mx
http://www.iquimica.unam.mx/departamentos/qorg/95-deps/qo/102-
dralejandrocorderoiq-alias
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600051.
Scheme 2. Proposed radical-ionic sequence based on an ATRA reaction.
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starting material substituents, as both the radical addition and ously converted into their corresponding epoxides upon treat-
the iodine transfer are highly regioselective.
ment with base.[6]
We reasoned that the acid-catalyzed lactonization would be
easier by using a carboxylic acid instead of an ester. Therefore,
iodoacetic acid was used as the radical precursor. In 2001,
Oshima[9] reported the use of this carboxylic acid in radical re-
actions. We considered that this reagent could serve not only
as the radical precursor but also as the acid catalyst for the
ionic step. Thus, we proceeded to examine the radical reaction
between iodoacetic acid (6b) and allylic alcohols 7a and 7b
under the reaction conditions described in Table 1.
As shown in the Table 1, the reaction between iodoacetic
acid (6b) and allylic alcohol 7a with triethylborane/O2 as the
radical initiator afforded a complex mixture of products
(Table 1, Entry 1). However, when DLP was used instead, a sepa-
rable mixture of diastereomeric lactones 10a and 10b[10] were
isolated in 53 % combined yield without any trace amount of
the ATRA adduct (Table 1, Entry 2). When allylic alcohol 7b[11]
was submitted to the same reaction conditions, lactones 11a
and 11b were obtained in 61 % combined yield (again as a
separable mixture of diastereomers). The amount of iodoacetic
acid was decreased to 1.2 equiv. (Table 1, Entry 4) and increased
to 3 equiv. (Table 1, Entry 5), but in both cases, the yield
dropped to 32 and 17 % yield, respectively. In the former case,
the reaction did not reach completion, and in the latter one, a
series of side products were formed along with the desired lact-
Results and Discussion
The new protocol started with the reaction between ethyl iodo-
acetate (6a) and known allylic alcohol 7a[8] (Scheme 3). The
radical step could be initiated with either Et3B/O2 (0.6 equiv.
added portionwise) or with lauroyl peroxide (DLP, 0.3 equiv.
added portionwise) in refluxing 1,2-dichloroethane (1,2-DCE) to
give hydroxy ester 8a in 65 and 45 % yield, respectively. How-
ever, when 8a was treated under a variety of acidic conditions
[trifluoroacetic acid (TFA), para-toluenesulfonic acid (PTSA), HCl,
or heating], 10 was not observed, but a complex mixture of
degradation products was formed instead. Basic conditions
were not evaluated because similar ATRA adducts were previ-
Scheme 3. Initial attempts for iodolactonization by using iodoacetate 6a as
the radical precursor (DCM = dichloromethane).
Table 1. Sequential ATRA-lactonization reaction.[a]
3
[a] The relative stereochemistry was determined by analyzing the vicinal coupling constants. The trans diastereomers have JH4,H5 values of approximately
3
8 Hz, whereas the cis stereoisomers have JH4,H5 values in the range of 2–3 Hz.
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ones. Different solvents and temperatures were employed, but addition of TFA, but the problem was circumvented by treating
modest yields were observed both at lower (in AcOEt, Table 1, the crude reaction mixture with oxalyl chloride (Method C). Dis-
Entry 6) and higher temperatures (in toluene, Table 1, Entry 7). appointingly, substrate 7r,[17] which also contains a tertiary al-
cohol, failed to produce the expected products, and 7r was
recovered after several hours of reaction time and the employ-
ment of an excess amount of DLP. Next, substituted olefins 7s
and 7t[18] were studied as the substrates (Table 2, Entries 12
and 13). For these cases, the radical-ionic sequence was suc-
cessful but afforded moderate yields of product (30 and 47 %,
respectively), most likely because of the higher stability of the
generated tertiary radical, which causes the iodine transfer to
be less efficient.[19] However, the isolation of hydroxylactone
31 suggests that the competitive kinetic lactonization of the
respective ATRA adduct is taking place. Interestingly, both lact-
ones 30 and 32 were isolated as single diastereomers, although
their relative stereochemistry could not be firmly established.
Finally, a control experiment was carried out with iodoacetic
acid (6b) and allylic alcohol 7b (Table 2, Entry 14). As expected,
no reaction took place in the absence of the radical initiator,
and the intact starting materials were recovered after several
hours of reaction time, which demonstrates that the process
proceeds through a radical pathway.
To further demonstrate the synthetic utility of this method,
we applied it to the synthesis of (–)-de-O-methylcentrolobine
(35),[20] a tetrahydropirane natural product, which was isolated
from some Centrolobium species that have significant antileish-
manial activity and for which only one racemic[21a] and one
asymmetric[21b] synthesis have been reported. Our strategy is
based on the use of a lactone such as (S)-33, which could easily
be prepared by applying our method to an enantioenriched
allylic alcohol. Thus, the simple addition of 34 to lactone 33
and the subsequent stereoselective reduction of the resulting
lactol[22] would provide the total synthesis of 35, after the re-
moval of the protecting groups (Scheme 4).
Hence, the synthesis of 35 commenced with the preparation
of enantiomerically enriched allylic alcohol 38 (Scheme 5). To
this end, known epoxide 36[23] (81 % ee) was subjected to me-
sylation (97 % yield) followed by a substitution reaction with
NaI to afford the corresponding iodide, which was treated with
Zn dust to provide the desired optically active allylic alcohol
38a in 62 % yield for the two steps. From this point, the end-
game to prepare 35 was straightforward. The treatment of 38
with our developed reaction conditions allowed for the prepa-
ration of the expected iodolactones, which were not isolated
but directly reduced by switching the solvent to benzene and
treating with Bu3SnH/azobis(isobutyronitrile) (AIBN). Under
these conditions, the iodine atom was cleanly removed to ren-
der lactone (S)-33a in 70 % yield (over two steps). When (S)-33a
was added to a preformed solution of the lithium derivative of
34a,[24] the corresponding lactol was formed and then directly
submitted to the reduction with Et3SiH and BF3·OEt2. To our
delight, the addition/reduction sequence worked well, and tet-
rahydropirane 39 was isolated in 50 % yield (over two steps) as
a single cis diastereomer. The final double hydrogenolysis of the
benzyl groups by using Pd(OH)2 under H2 in methanol com-
pleted the total synthesis of (–)-de-O-methylcentrolobine (35)
Finally, other radical initiators were examined. Unfortunately,
neither dicumyl peroxide (DCP, Table 1, Entry 8) nor benzoyl
peroxide (DBP, Table 1, Entry 9) provided better yields. Thus,
the best reaction conditions for the iodolactonization involved
1 equiv. of the corresponding allylic alcohol, 2 equiv. of iodoa-
cetic acid, and DLP (substoichiometric amount) in refluxing 1,2-
DCE.
Having determined the optimal reaction conditions, we pro-
ceeded to study the scope and limitations of the method. The
results are summarized in the Table 2.
Interestingly, secondary allylic alcohols such as 7c[12] af-
forded the expected lactones 12a and 12b in moderate yield
(Table 2, Entry 1). With substrates 7d[12] and 7e (Table 2, En-
tries 2 and 3), rearranged allylic products 13 and 14 were ob-
served. These latter results seem to occur when electron-rich
benzylic alcohols are employed as substrates, as the acidic me-
dia probably catalyzes the dehydration of the alcohol. Good
results were obtained when other secondary alcohols were em-
ployed (Table 2, Entry 4). A number of functional groups, such
as the acid-sensitive tert-butyldimethylsilyl (TBS; i.e., 7g) and
methoxymethyl (MOM; i.e., 7h) protecting groups, were well
tolerated under these reaction conditions. Esters [pivaloyloxy
(OPiv); i.e., 7i] and carbamates (i.e., 7j) were also suitable pro-
tecting groups for the reactions conditions and rendered the
corresponding lactones 18a and 18b as well as 19a and 19b
in good yields. A remarkable example involves compound 7f,
which has a free hydroxyl group and formed lactones 15a and
15b in 70 % yield. In some experiments (Table 2, Entries 5–10),
the reaction afforded a mixture of the expected lactones along
with the ATRA adducts, which indicated that the radical step
was efficient but the ionic lactonization was not. Thus, in the
cases when the lactonization step had not reached completion,
20 mol-% of TFA was added at the end of the radical process
(one pot), and the reaction mixture was stirred at room temp.
until all of the ATRA adduct was consumed (monitored by TLC
analysis). Under these conditions (Method B), other secondary
alcohols such as 7k[13] provided lactones 20a and 20b in 54 %
yield, and -proline derivative 7l allowed for the construction of
L
bicyclic compounds 21a and 21b in 71 % yield (Table 2, En-
tries 5 and 6). The construction of spirocyclic systems is also
possible by using this method (Table 2, Entry 7). Alcohols 7m–
7o,[14] which are easily prepared by the addition of vinylmagne-
sium bromide to the corresponding cyclic ketones, provided
the [5,6], [6,6], and [6,7] ring systems of spirocyclic lactones 22,
23, and 24, respectively, in good yields. The same substrates
7m–7o were treated with iodopropionic acid[15] (6c), a precur-
sor of secondary radicals, to prepare the substituted spirolac-
tones 25a/25b–27a/27b, respectively, in good yields and varia-
ble diastereoselectivities (Table 2, Entry 8). Complex tricyclic
structures such as 28a and 28b (Table 2, Entry 9) that start
from alcohol 7p[16] as well as lactones 29a and 29b that have
a sterically congested quaternary center (Table 2, Entry 10) can
be easily assembled by using this method. In the latter case, in 70 % yield. The spectroscopic and physical data of 35 were
no lactonization occurred after the radical step even with the in full agreement with those reported in the literature.[21b]
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Table 2. Scope and limitations of the intermolecular iodolactonization (Ts = p-tolylsulfonyl, n.r.: no reaction). Method A: DLP (0.1 to 0.3 equiv. added portion-
wise), 1,2-DCE, reflux; Method B: DLP (0.1 to 0.3 equiv. added portionwise), 1,2-DCE, reflux and then TFA (20 mol-%) room temp.; Method C: (i) DLP (0.1 to
0.3 equiv. added portionwise), 1,2-DCE, reflux, (ii) (COCl)2, NEt3, N,N-dimethylformamide (DMF, cat.), DCM, 0 °C.
[a] The stereochemistry was determined by the H4-H5 coupling constant values. [b] The stereochemistry was determined by NOESY experiments (see Support-
ing Information).
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ments, which afforded a wide variety of iodolactones with di-
verse functionalities. Carbobenzyloxy (Cbz), TBS, MOM, and Piv
protecting groups as well as unprotected hydroxyl groups toler-
ated the reaction conditions. Mono-, di-, and trisubstituted ole-
fins rendered the expected lactones in variable yields, but the
diversely obtained structures, such as fused bicycles or spirocy-
cles of different ring sizes, give this method wide potential for
the synthesis of complex molecules. Additionally, the utility of
this strategy was demonstrated in the synthesis of (–)-de-O-
methylcentrolobine (35). Efforts to take advantage of the iodine
atom in further chemical manipulations and applications to to-
tal synthesis are currently under progress and will be reported
in due course.
Scheme 4. Strategy for the synthesis of (–)-de-O-methylcentrolobine (PG =
protecting group).
Experimental Section
General Methods: All operations were carried out under argon.
Anhydrous solvents were obtained by distillation under an inert
atmosphere. Column chromatography was performed with
70e230 mesh silica gel. All reagents and solvents were obtained
from commercial suppliers and used without further purification.
All compounds were characterized by IR spectra that were recorded
on a Bruker Tensor 27 spectrophotometer using film and KBr tech-
niques. All IR data are expressed in wavenumbers [cm–1], and the
signals are described by intensity as weak (w), medium (m), or
strong (s). Melting points were obtained on a Melt-Temp II appara-
tus. Specific rotations were measured on a Perkin–Elmer 343 pola-
rimeter by using a sodium lamp (589 nm) and a 1 dM quartz cell.
The NMR spectroscopic data were recorded with a JEOL Eclipse
þ300 (300 MHz), a Bruker Avance III (400 MHz), or a Varian Unity
Inova (500 MHz), and the appropriates deuterated solvents were
employed. Chemical shifts are reported parts per million (δ) relative
to TMS. COSY, NOESY, and heteronuclear single quantum correlation
(HSQC) experiments were carried out to confirm the assignments
and relative stereochemistry of the compounds. The MS-FABþ and
mass spectrometry-direct analysis in real time (MS-DART) spectra
were obtained on a JEOL SX 102A and a JEOL DART AccuTOF JMS-
T100CC, respectively. The values of the signals are expressed in
mass/charge units (m/z) followed by the relative intensity relative
to a 100 % base peak.
General Procedures for the Radical-Ionic Iodolactonization Re-
action
Method A: A solution of the corresponding allylic alcohol (1 mmol)
and the iodocarboxylic acid (2 mmol) in 1,2-dichloroethane (5 mL)
was heated at reflux under argon for 5 min. Then, lauroyl peroxide
(10 mol-%) was added every 1.5 h until the starting material was
completely consumed (monitored by TLC analysis). The solvent was
removed under reduced pressure, and the residue was purified by
flash column chromatography (silica gel and a short pad of basic
alumina on the top).
Scheme 5. Enantioselective total synthesis of (–)-de-O-methylcentrolobine
(35, Ms = methylsulfonyl, THF = tetrahydrofuran).
Method B: A solution of the corresponding allylic alcohol (1 mmol)
and the iodocarboxylic acid (2 mmol) in 1,2-dichloroethane (5 mL)
was heated at reflux under argon for 5 min. Then, lauroyl peroxide
(10 mol-%) was added every 1.5 h until the allylic alcohol was com-
pletely consumed (monitored by TLC analysis). Then, the mixture
was cooled to room temperature, diluted with 1,2-DCE (5 mL), and
covered from light. Trifluoroacetic acid (20 mol-%) was added to
the reaction mixture, which was then stirred for an additional 3 h
at room temp. The solvent was removed under reduced pressure,
and the residue was purified by flash column chromatography (sil-
Conclusions
Herein, we have reported a method based on a radical-ionic
sequence between an allylic alcohol and an α-iodo acid in the
presence of substoichiometric amounts of lauroyl peroxide to
produce the ATRA adduct that subsequently underwent an
acid-mediated lactonization reaction. This chemical transforma-
tion can be described as the first intermolecular iodolactoniza-
tion. The scope of the reaction was evaluated by 22 experi- ica gel and a short pad of basic alumina on the top).
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Method C: A solution of the corresponding allylic alcohol (1 mmol)
and the iodocarboxylic acid (2 mmol) in 1,2-dichloroethane (5 mL)
was heated at reflux under argon for 5 min. Then, lauroyl peroxide
(10 mol-%) was added every 1.5 h until the allylic alcohol was com-
pletely consumed (monitored by TLC analysis). Then, the mixture
was cooled to 0 °C, diluted with 1,2-DCE (5 mL), and covered from
light. Triethylamine (6 mmol), oxalyl chloride (2.5 mmol), and DMF
(1 drop) were successively added to the reaction mixture, which
was then stirred at 0 °C for an additional 2 h. Finally, the reaction
was quenched with water, and the resulting mixture was extracted
with CH2Cl2. The organic layer was dried and purified by flash col-
umn chromatography (silica gel and a short pad of basic alumina
on the top).
general procedure for Method A to give a separable mixture of
diastereomers trans-12a and cis-12b (30 % yield).
(5R*,6S*)-5-Iodo-6-(naphthalen-1-yl)tetrahydro-2H-pyran-2-one
(12a): White solid; m.p. 123–125 °C, decomposes). IR (film): ν = 2952
˜
(s), 2918 (s), 2850 (s), 1702 (s), 1598 (w), 1513 (w), 1466 (m), 1410
(m), 1350 (w), 1331 (w), 1298 (m), 1244 (m), 1195 (m), 1133 (w),
1065 (w), 1011 (m), 962 (m), 939 (m), 911 (m), 777 (m), 731
(m) cm–1 1H NMR (400 MHz, CDCl3): δ = 7.94–7.85 (m, 3 H), 7.61
.
(ddd, J = 8.5, 6.8, 1.5 Hz, 1 H), 7.54 (ddd, J = 8.0, 6.8, 1.2 Hz, 1 H),
7.49 (dd, J = 8.1, 7.2 Hz, 1 H), 7.43 (dt, J = 7.2, 1.0 Hz, 1 H), 6.45 (d,
J = 4.6 Hz, 1 H), 4.79 (q, J = 4.9 Hz, 1 H), 3.02 (dt, J = 18.5, 8.2 Hz,
1 H), 2.83 (dtd, J = 18.4, 5.1, 0.5 Hz, 1 H), 2.19 (ddd, J = 8.6, 5.4,
4.5 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1, 134.0, 133.8,
129.9 (2 C), 129.5, 127.3, 126.3, 125.3, 124.4, 122.5, 85.6, 29.8, 28.3,
24.0 ppm. HRMS (DART) m/z calcd. for C15H14IO2 [M + H]+:
353.00385, found 353.00431.
5-Iodo-6-phenyltetrahydro-2H-pyran-2-one (10a and 10b): Iodo-
acetic acid (6b) and alcohol 7a[8] were used in the general proce-
dure for Method A to give a separable mixture of diastereomers
trans-10a and cis-10b (53 % yield).
(5R*,6R*)-5-Iodo-6-(naphthalen-1-yl)tetrahydro-2H-pyran-2-one
(12b): Yellow solid; m.p. 109–111 °C (decomposes). IR (film): ν =
˜
(5R*,6S*)-5-Iodo-6-phenyltetrahydro-2H-pyran-2-one
(10a):
1
2919 (m), 2850 (m), 1740 (s), 1598 (w), 1511 (w), 1445 (w), 1410 (w),
1334 (m), 1304 (m), 1242 (m), 1228 (m), 1193 (m), 1164 (m), 1133
(w), 1095 (m), 1059 (m), 1015 (w), 953 (w), 915 (m), 901 (w), 798
White solid. H NMR (300 MHz, CDCl3): δ = 7.46–7.29 (m, 5 H), 5.55
(d, J = 7.9 Hz, 1 H), 4.42 (td, J = 7.9, 4.8 Hz, 1 H), 2.85 (dt, J = 18.1,
7.0 Hz, 1 H), 2.71 (ddd, J = 18.1, 7.3, 6.4 Hz, 1 H), 2.51–2.32 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.3, 137.8, 129.3, 128.9 (2
C), 127.0 (2 C), 87.3, 30.8, 30.7, 24.5 ppm. The analytical data are in
full agreement with those reported by Gao.[10]
1
(m), 786 (m), 774 (m), 732 (w) cm–1. H NMR (400 MHz, CDCl3): δ =
7.92 (d, J = 7.4 Hz, 1 H), 7.86 (d, J = 8.3 Hz, 1 H), 7.74 (dd, J = 7.3,
1.4 Hz, 1 H), 7.67 (d, J = 8.6 Hz, 1 H), 7.58–7.47 (m, 3 H), 5.50 (s, 1
H), 4.99 (q, J = 2.7 Hz, 1 H), 3.18–3.05 (m, 1 H), 2.91 (ddd, J = 18.9,
7.3, 1.9 Hz, 1 H), 2.73 (dddd, J = 14.5, 10.9, 7.4, 3.7 Hz, 1 H), 2.52
(dddd, J = 14.9, 8.0, 3.7, 1.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.1, 133.6, 133.3, 129.8, 129.3, 128.9, 126.8, 125.7,
125.4, 125.3, 120.9, 79.6, 32.3, 31.1, 28.7 ppm. HRMS (DART): calcd.
for C15H14IO2 [M + H]+ 353.00385; found 353.00429.
(5R*,6R*)-5-Iodo-6-phenyltetrahydro-2H-pyran-2-one
(10b):
White needles; m.p. 110 °C. IR (KBr): ν = 3431 (w), 2961 (w), 2930
˜
(w), 1718 (s), 1454 (m), 1310 (m), 1234 (m), 1058 (m), 699
(m) cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.42–7.31 (m, 5 H), 4.88 (d,
J = 2.0 Hz, 1 H), 4.66 (dd, J = 5.7, 2.7 Hz, 1 H), 3.04 (ddd, J = 18.8,
10.6, 8.1 Hz, 1 H), 2.82 (dddd, J = 18.7, 6.8, 2.4, 0.7 Hz, 1 H), 2.60–
2.43 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.7, 138.8,
128.7, 128.5 (2 C), 125.4 (2 C), 82.4, 32.8, 31.0, 28.5 ppm. HRMS
(FAB+): calcd. for C11H12IO2 [M + H]+ 302.9882; found 302.9889.
(E)-3-(4-Methoxyphenyl)allyl 2-Iodoacetate (13): Iodoacetic acid
(6b) and allylic alcohol 7d[12] were used in the general procedure
for Method A to give 13 (25 % yield) as a colorless oil. IR (film): ν =
˜
3037 (w), 3003 (w), 2955 (m), 2933 (m), 2836 (w), 1730 (s), 1655 (w),
1607 (s), 1576 (w), 1511 (s), 1461 (m), 1442 (m), 1417 (m), 1374 (w),
1302 (m), 1250 (s), 1175 (s), 1118 (m), 1089 (s), 1032 (s), 965 (s), 917
5-Iodo-6-phenethyltetrahydro-2H-pyran-2-one (11a and 11b):
Iodoacetic acid (6b) and allylic alcohol 7b[11] were used in the gen-
eral procedure for Method A to give a separable mixture of dia-
stereomers trans-11a and cis-11b (61 % yield).
(w), 839 (m), 802 (w), 757 (w), 659 (w) cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.33 (d, J = 8.4 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 6.65
(d, J = 16.4 Hz, 1 H), 6.15 (dt, J = 15.8, 6.7 Hz, 1 H), 4.77 (dd, J = 6.7,
1.3 Hz, 2 H), 3.81 (s, 3 H), 3.73 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.7, 159.9, 135.0, 128.9, 128.1 (2 C), 120.0, 114.2 (2 C),
67.1, 55.5, –5.3 ppm. HRMS (DART): calcd. for C12H13IO3 [M]+
331.99094; found 331.99157.
(5R*,6S*)-5-Iodo-6-phenethyltetrahydro-2H-pyran-2-one (11a):
White solid; m.p. 82–83 °C. IR (KCl): ν = 3025 (w), 2927 (w), 2855
˜
(w), 1769 (s), 1450 (m), 1193 (m), 986 (m), 749 (m), 699 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.16 (m, 5 H), 4.39 (td, J = 8.0,
6.3 Hz, 1 H), 4.02 (ddd, J = 10.2, 7.9, 3.3 Hz, 1 H), 2.97 (ddd, J = 13.7,
8.8, 4.7 Hz, 1 H), 2.72 (ddd, J = 13.8, 8.9, 7.5 Hz, 1 H), 2.62–2.43 (m,
3 H), 2.29–2.17 (m, 1 H), 2.16–2.06 (m, 1 H), 2.06–1.94 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 176.3, 140.1, 128.73 (2 C), 128.69 (2
C), 126.5, 82.3, 38.7, 37.6, 35.1, 29.1, 28.8 ppm. HRMS (DART): calcd.
for C13H16IO2 [M + H]+ 331.01950; found 331.02086.
(3,4-Dihydronaphthalen-2-yl)methyl 2-Iodoacetate (14): Iodo-
acetic acid (6b) and allylic alcohol 7e were used in the general
procedure for Method A to give 14 (63 % yield). IR (film): ν = 3058
˜
(m), 3015 (m), 2930 (s), 2885 (m), 2830 (m), 1733 (s), 1485 (w), 1452
(w), 1436 (w), 1415 (w), 1264 (s), 1153 (w), 1087 (m), 966 (m), 885
(w), 856 (w), 757 (m) cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.15–7.03
(m, 4 H), 6.51 (s, 1 H), 4.74 (s, 2 H), 3.74 (s, 2 H), 2.86 (t, J = 8.2 Hz,
2 H), 2.32 (t, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
168.7, 135.0, 134.4, 133.5, 127.55, 127.50, 126.7, 126.5, 126.4, 68.9,
27.8, 24.7, –5.5 ppm. HRMS (DART): calcd. for C13H17INO2 [M + NH4]+
346.03040; found 346.03052.
(5R*,6R*)-5-Iodo-6-phenethyltetrahydro-2H-pyran-2-one (11b):
Orange needles; m.p. 104–105 °C. IR (KBr): ν = 3027 (w), 2942 (m),
˜
2854 (w), 1725 (s), 1497 (m), 1238 (m), 1057 (m), 737 (m) cm–1. H
1
NMR (400 MHz, CDCl3): δ = 7.32–7.18 (m, 5 H), 4.44 (qd, J = 3.4,
1.4 Hz, 1 H), 3.42 (ddd, J = 8.1, 4.7, 2.0 Hz, 1 H), 2.90 (ddd, J = 18.7,
10.7, 8.0 Hz, 1 H), 2.82–2.72 (m, 2 H), 2.66 (dddd, J = 18.7, 6.5, 2.7,
0.9 Hz, 1 H), 2.37–2.23 (m, 2 H), 2.17 (dtd, J = 14.2, 8.2, 6.1 Hz, 1 H),
1.82 (dddd, J = 14.1, 8.7, 7.6, 4.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.9, 140.5, 128.8 (2 C), 128.6 (2 C), 126.5, 80.5, 39.6,
31.0, 30.6, 30.3, 28.4 ppm. HRMS (FAB+): calcd. for C13H16IO2 [M +
H]+ 331.0195; found 331.0195.
6-(4-Hydroxyphenethyl)-5-iodotetrahydro-2H-pyran-2-one (15a
and 15b): Iodoacetic acid (6b) and allylic alcohol 7f were used in
the general procedure for Method A to give a separable mixture of
diastereomers trans-15a and cis-15b (70 % yield).
(5R*,6S*)-6-(4-Hydroxyphenethyl)-5-iodotetrahydro-2H-pyran-
5-Iodo-6-(naphthalen-1-yl)tetrahydro-2H-pyran-2-one (12a and
12b): Iodoacetic acid (6b) and allylic alcohol 7c[12] were used in the
2-one (15a): White solid; m.p. 143–144 °C. IR (film): ν = 3368 (br.
m), 3018 (w), 2923 (s), 2852 (m), 1716 (s), 1613 (m), 1596 (w), 1514
˜
Eur. J. Org. Chem. 2016, 1739–1750
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1744
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(s), 1450 (m), 1360 (m), 1228 (s), 1173 (m), 1057 (m), 1025 (m), 986
(w), 923 (w), 883 (w), 829 (m), 759 (w), 716 (w) cm–1 1H NMR
(m), 2925 (m), 2852 (w), 1733 (s), 1611 (w), 1510 (s), 1452 (w), 1232
1
.
(s), 1199 (m), 1151 (s), 1077 (m), 1004 (s), 921 (w), 831 (s) cm–1. H
(400 MHz, [D6]acetone): δ = 8.13 (s, 1 H), 7.06 (d, J = 8.8 Hz, 2 H),
6.77 (d, J = 8.5 Hz), 4.53 (td, J = 8.5, 2.9 Hz, 1 H), 4.45 (td, J = 8.5,
4.7 Hz, 1 H), 2.77 (ddd, J = 14.5, 10.1, 4.9 Hz, 1 H), 2.70–2.59 (m, 3
H), 2.57–2.49 (m, 1 H), 2.47–2.36 (m, 1 H), 2.28 (dddd, J = 14.2,
9.9, 6.9, 2.9 Hz, 1 H), 2.03–1.94 (m, 1 H) ppm. 13C NMR (100 MHz,
[D6]acetone): δ = 169.5, 156.5, 132.5, 130.2 (2 C), 116.1 (2 C), 84.4,
37.8, 32.5, 31.2, 30.6, 25.3 ppm. HRMS (DART): calcd. for C13H16IO3
[M + H]+ 347.01441; found 347.01476.
NMR (400 MHz, CDCl3): δ = 7.15–7.05 (m, 2 H), 7.02–6.92 (m, 2 H),
5.15 (s, J = 2.4 Hz, 2 H), 4.47 (td, J = 8.9, 2.7 Hz, 1 H), 4.12–4.06 (m,
1 H), 3.48 (s, J = 1.6 Hz, 3 H), 2.88–2.79 (m, 1 H), 2.73–2.30 (m, 5 H),
2.13–1.84 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.9, 155.7,
133.9, 129.6 (2 C), 116.5 (2 C), 94.6, 83.9, 56.1, 36.8, 32.1, 30.9, 30.0,
22.6 ppm. HRMS (DART): calcd. for C15H20IO4 [M + H]+ 391.04063;
found 391.04137.
(5R*,6R*)-5-Iodo-6-[4-(methoxymethoxy)phenethyl]tetrahydro-
(5R*,6R*)-6-(4-Hydroxyphenethyl)-5-iodotetrahydro-2H-pyran-
2H-pyran-2-one (17b): Colorless oil. IR (film): ν = 3446 (m), 2951
˜
2-one (15b): Yellow solid; m.p. 139–140 °C. IR (film): ν = 3349 (br.
˜
(s), 2826 (m), 1736 (w), 1510 (s), 1446 (w), 1353 (w), 1234 (s), 1198
(m), 1151 (s), 1078 (m), 1056 (m), 1003 (s), 920 (m), 829 (m) cm–1
.
m), 3018 (m), 2924 (s), 2853 (m), 1712 (s), 1612 (w), 1595 (w), 1514
1H NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 8.8 Hz, 2 H), 6.96 (d, J =
8.8 Hz, 2 H), 5.15 (s, 2 H), 4.43 (dd, J = 5.4, 2.8 Hz, 1 H), 3.48 (s, 3
H), 3.41 (ddd, J = 8.0, 4.4, 2.0 Hz, 1 H), 2.90 (ddd, J = 18.7, 10.6,
8.1 Hz, 1 H), 2.78–2.60 (m, 3 H), 2.36–2.23 (m, 2 H), 2.17–2.08 (m, 1
H), 1.82–1.73 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.9,
155.8, 133.8, 129.5 (2 C), 116.6 (2 C), 94.6, 80.4, 56.1, 39.8, 30.9, 30.4,
29.7, 28.4 ppm. HRMS (DART): calcd. for C15H20IO4 391.04063 [M +
H]+; found 391.04027.
(s), 1447 (m), 1357 (m), 1243 (s), 1173 (m), 1116 (w), 1090 (w), 1056
(m), 922 (w), 887 (w), 830 (m), 760 (w) cm–1 1H NMR (400 MHz,
.
[D6]acetone): δ = 8.14 (s, 1 H), 7.06 (d, J = 8.4 Hz, 2 H), 6.76 (d, J =
8.5 Hz, 2 H), 4.82 (td, J = 3.4, 2.0 Hz, 1 H), 3.58 (ddd, J = 7.2, 5.2,
1.9 Hz, 1 H), 2.76–2.60 (m, 4 H), 2.57–2.47 (m, 1 H), 2.30 (ddt, J =
14.9, 7.2, 3.1 Hz, 1 H), 1.96 (dddd, J = 13.9, 9.0, 7.8, 6.2 Hz, 1 H), 1.80
(dddd, J = 13.7, 9.2, 7.2, 5.1 Hz, 1 H) ppm. 13C NMR (100 MHz,
[D6]acetone): δ = 168.8, 156.6, 132.5, 130.2 (2 C), 116.1, 116.0, 80.8,
40.9, 34.1, 31.6, 30.3, 28.9 ppm. HRMS (DART): calcd. for C13H16IO3
[M + H]+ 347.01441; found 347.01447.
4-[2-(3-Iodo-6-oxotetrahydro-2H-pyran-2-yl)ethyl]phenyl Pival-
ate (18a and 18b): Iodoacetic acid (6b) and allylic alcohol 7i were
used in the general procedure for Method A to give the separable
mixture of diastereomers trans-18a and cis-18b (79 % yield).
6-{4-[(tert-Butyldimethylsilyl)oxy]phenethyl}-5-iodotetrahydro-
2H-pyran-2-one (16a and 16b): Iodoacetic acid (6b) and allylic
alcohol 7g were used in the general procedure for Method A to
give a separable mixture of diastereomers trans-16a and cis-16b
(66 % yield).
4-{2-[(2R*,3S*)-3-Iodo-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-
phenyl Pivalate (18a): Pale yellow solid; m.p. 73–74 °C. IR (film):
ν = 3034 (w), 2970 (m), 2929 (m), 2872 (w), 1745 (s), 1605 (w), 1507
˜
(5R*,6S*)-6-{4-[(tert-Butyldimethylsilyl)oxy]phenethyl}-5-iodo-
(m), 1479 (m), 1456 (m), 1417 (w), 1395 (w), 1366 (w), 1335 (w),
1278 (m), 1244 (m), 1199 (s), 1166 (s), 1100 (s), 1054 (m), 1028 (m),
tetrahydro-2H-pyran-2-one (16a): Green oil. IR (film): ν = 2955
˜
(m), 2929 (m), 2895 (m), 2857 (m), 1742 (s), 1609 (m), 1510 (s), 1471
985 (w), 941 (w), 896 (w), 854 (w), 794 (w), 759 (w) cm–1 1H NMR
.
(w), 1462 (w), 1387 (w), 1361 (w), 1334 (w), 1254 (s), 1202 (m), 1170
(400 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 8.4 Hz,
2 H), 4.46 (td, J = 9.0, 2.6 Hz, 1 H), 4.09 (td, J = 9.1, 4.9 Hz, 1 H), 2.89
(ddd, J = 14.3, 10.0, 4.7 Hz, 1 H), 2.79–2.71 (m, 1 H), 2.71–2.63 (m,
1 H), 2.59–2.46 (m, 2 H), 2.43–2.31 (m, 2 H), 2.01 (dtd, J = 14.1, 9.2,
4.7 Hz, 1 H), 1.35 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.3,
169.8, 149.5, 137.8, 129.5 (2 C), 121.6 (2 C), 83.8, 39.1, 36.6, 32.1,
31.0, 30.2, 27.2 (3 C), 22.5 ppm. HRMS (DART): calcd. for C18H24IO4
[M + H]+ 431.07193; found 431.07196.
(m), 1053 (w), 1028 (m), 914 (s), 839 (s), 780 (m) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.06 (d, J = 8.4 Hz, 2 H), 6.77 (d, J = 8.4 Hz,
2 H), 4.45 (td, J = 8.9, 2.7 Hz), 4.09 (td, J = 8.9, 5.1 Hz, 1 H), 2.83
(ddd, J = 14.3, 9.9, 4.9 Hz, 1 H), 2.73–2.62 (m, 2 H), 2.57 (dd, J = 8.2,
6.1 Hz, 1 H), 2.54–2.44 (m, 1 H), 2.42–2.27 (m, 2 H), 2.00 (dddd, J =
14.3, 9.3, 8.6, 4.8 Hz, 1 H), 0.98 (s, 9 H), 0.19 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.0, 154.1, 133.2, 129.5 (2 C), 120.2 (2 C),
84.1, 36.7, 32.1, 30.9, 30.0, 25.8 (3 C), 22.7, 18.3, –4.3 (2 C) ppm.
HRMS (DART): calcd. for C19H30IO3Si [M + H]+ 461.10089; found
461.10163.
4-{2-[(2R*,3R*)-3-Iodo-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-
phenyl Pivalate (18b): Green oil. IR (film): ν = 3033 (w), 2971 (m),
˜
2932 (m), 2871 (w), 1744 (s), 1605 (w), 1507 (m), 1479 (m), 1451 (m),
1415 (w), 1396 (m), 1350 (m), 1278 (m), 1237 (s), 1199 (s), 1166 (s),
1122 (s), 1056 (m), 1029 (m), 1018 (m), 922 (w), 896 (m), 853 (w),
(5R*,6R*)-6-{4-[(tert-Butyldimethylsilyl)oxy]phenethyl}-5-iodo-
tetrahydro-2H-pyran-2-one (16b): Green oil. IR (film): ν = 2954
˜
(m), 2929 (m), 2895 (m), 2857 (m), 1740 (s), 1608 (w), 1510 (s), 1471
794 (w), 759 (m) cm–1 1H NMR (400 MHz, CDCl3): δ = 7.20 (d, J =
.
(w), 1462 (w), 1448 (w), 1359 (w), 1254 (s), 1207 (w), 1170 (w), 1092
8.4 Hz, 2 H), 6.98 (d, J = 8.5 Hz, 2 H), 4.43 (q, J = 3.0 Hz, 1 H), 3.41
(ddd, J = 8.4, 4.3, 1.9 Hz, 1 H), 2.90 (ddd, J = 18.7, 10.6, 8.1 Hz, 1 H),
2.85–2.73 (m, 2 H), 2.67 (ddd, J = 18.9, 6.6, 3.0 Hz, 1 H), 2.38–2.23
(m, 2 H), 2.16 (dtd, J = 14.1, 8.1, 5.9 Hz, 1 H), 1.79 (dtd, J = 14.2, 8.2,
4.2 Hz, 1 H), 1.35 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.4,
168.9, 149.7, 137.8, 129.5 (2 C), 121.7 (2 C), 80.3, 39.7, 39.2, 30.9,
30.3, 30.0, 28.4, 27.3 (3 C) ppm. HRMS (DART): calcd. for C18H24IO4
[M + H]+ 431.07193; found 431.07199.
(w), 1055 (m), 1010 (w), 916 (s), 839 (s), 781 (m) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.04 (d, J = 8.4 Hz, 2 H), 6.76 (d, J = 8.5 Hz,
2 H), 4.43 (dddd, J = 4.0, 3.3, 2.1, 0.8 Hz, 1 H), 3.39 (ddd, J = 8.0, 4.8,
2.0 Hz, 1 H), 2.90 (ddd, J = 18.7, 10.8, 7.9 Hz, 1 H), 2.76–2.60 (m, 3
H), 2.38–2.21 (m, 2 H), 2.18–2.06 (m, 1 H), 1.78 (dddd, J = 14.1, 8.5,
7.7, 4.8 Hz, 1 H), 0.98 (s, 9 H), 0.19 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.8, 154.0, 132.9, 129.3 (2 C), 120.1 (2 C), 80.4, 39.6,
30.8, 30.2, 29.6, 28.3, 25.7 (3 C), 18.1, –4.4 (2 C) ppm. HRMS (DART):
calcd. for C19H30IO3Si [M + H]+ 461.10089; found 461.10212.
Benzyl {4-[2-(3-Iodo-6-oxotetrahydro-2H-pyran-2-yl)ethyl]-
phenyl}(methyl)carbamate (19a and 19b): Iodoacetic acid (6b)
and allylic alcohol 7j were used in the general procedure for
Method A to give a separable mixture of diastereomers trans-19a
and cis-19b (64 % yield).
5-Iodo-6-[4-(methoxymethoxy)phenethyl]tetrahydro-2H-pyran-
2-one (17a and 17b): Iodoacetic acid (6b) and allylic alcohol 7h
were used in the general procedure for Method A to give a separa-
ble mixture of diastereomers trans-17a and cis-17b (64 % combined
yield).
Benzyl (4-{2-[(2R*,3S*)-3-Iodo-6-oxotetrahydro-2H-pyran-2-
yl]ethyl}phenyl)(methyl)carbamate (19a): Colorless oil. IR (film):
(5R*,6S*)-5-Iodo-6-[4-(methoxymethoxy)phenethyl]tetrahydro-
2H-pyran-2-one (17a): Colorless oil. IR (film): ν = 3445 (m), 2951
ν = 3458 (br. w), 3032 (m), 2952 (s), 2925 (s), 1734 (s), 1696 (s), 1513
˜
˜
Eur. J. Org. Chem. 2016, 1739–1750
www.eurjoc.org
1745
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(m), 1451 (m), 1385 (m), 1345 (s), 1246 (m), 1149 (s), 1110 (w), 1025
(m), 841 (w), 732 (s), 696 (s), 598 (m), 573 (m), 528 (m) cm–1 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.28 (m, 5 H), 7.23–7.16 (m, 4 H),
5.16 (s, 2 H), 4.47 (td, J = 9.0, 2.7 Hz, 1 H), 4.09 (td, J = 8.8, 5.2 Hz,
1 H), 3.31 (s, 3 H), 2.90 (ddd, J = 13.8, 10.1, 4.8 Hz, 1 H), 2.77–2.47
(m, 4 H), 2.43–2.31 (m, 2 H), 2.10–1.95 (m, 1 H) ppm. 13C NMR
3.50–3.42 (m, 1 H), 3.27–3.18 (m, 1 H), 2.93 (ddd, J = 18.7, 10.0,
8.5 Hz, 1 H), 2.70 (ddd, J = 18.4, 7.5, 2.7 Hz, 1 H), 2.45 (s, 3 H), 2.44–
2.31 (m, 2 H), 2.29–2.14 (m, 1 H), 1.86–1.69 (m, 1 H), 1.57 (dtt, J =
12.8, 7.4, 3.9 Hz, 1 H), 1.48–1.29 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.8, 144.3, 133.8, 130.1 (2 C), 127.9 (2 C), 82.2, 64.4,
50.0, 31.3, 30.0, 28.8, 26.7, 24.4, 21.7 ppm. HRMS (FAB+): calcd. for
.
(100 MHz, CDCl3): δ = 169.9, 155.5, 141.5, 138.5, 136.7, 129.0 (2 C), C16H21NSO4I 450.02360; found 450.02480.
128.5 (2 C), 128.0 (2 C), 127.8, 125.9 (2 C), 83.9, 67.4, 37.9, 36.5, 32.2,
(–)-(5R,6R)-5-Iodo-6-[(S)-1-tosylpyrrolidin-2-yl]tetrahydro-2H-
pyran-2-one (21b): White-yellow solid; m.p. 168–169 °C. [α]D25
–58.4 (c = 0.68, CHCl3). IR (KBr): ν = 3421 (w), 2956 (m), 2924 (m),
31.0, 30.3, 22.5 ppm. HRMS (DART): calcd. for C22H25INO4 [M + H]+
494.08283; found 494.08284.
=
˜
Benzyl (4-{2-[(2R*,3R*)-3-Iodo-6-oxotetrahydro-2H-pyran-2- 1740 (s), 1455 (w), 1341 (s), 1203 (m), 1158 (s), 1090 (s), 1022 (m),
yl]ethyl}phenyl)(methyl)carbamate (19b): Colorless oil. IR (film):
817 (w), 665 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J =
ν = 3458 (br. w), 3032 (m), 2949 (s), 2927 (s), 2861 (m), 1735 (s),
8.3 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 2 H), 4.88 (dd, J = 8.1, 4.4 Hz, 1 H),
˜
1609 (w), 1513 (s), 1445 (m), 1386 (m), 1345 (s), 1237 (m), 1207 (w), 4.34–4.27 (m, 1 H), 4.12–4.05 (m, 1 H), 3.53–3.42 (m, 1 H), 3.27 (dt,
1149 (s), 1111 (w), 1053 (s), 1010 (m), 920 (w), 840 (m), 762 (m), 733 J = 10.9, 6.8 Hz, 1 H), 2.85–2.74 (m, 1 H), 2.65–2.57 (m, 1 H), 2.57–
(s), 696 (s), 598 (w), 574 (w), 537 (m) cm–1. 1H NMR (400 MHz, CDCl3): 2.49 (m, 1 H), 2.45 (s, 3 H), 2.44–2.36 (m, 1 H), 1.92–1.81 (m, 2 H),
δ = 7.35–7.27 (m, 5 H), 7.21–7.16 (m, 4 H), 5.16 (s, 2 H), 4.44 (q, J = 1.59–1.39 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.3, 144.1,
3.0 Hz, 1 H), 3.42 (ddd, J = 8.3, 4.5, 2.0 Hz), 3.30 (s, 3 H), 2.90 (ddd,
J = 18.8, 10.8, 8.0 Hz, 1 H), 2.83–2.59 (m, 3 H), 2.36–2.10 (m, 3 H),
1.84–1.76 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.9, 155.5,
141.6, 138.4, 136.7, 129.0 (2 C), 128.5 (2 C), 128.0 (2 C), 127.8, 126.0
(2 C), 80.4, 67.4, 39.6, 37.9, 30.9, 30.3, 30.0, 28.4 ppm. HRMS (DART):
calcd. for C22H25INO4 [M + H]+ 494.08283; found 494.08289.
134.1, 130.0 (2 C), 127.8 (2 C), 85.9, 61.8, 49.7, 30.9, 30.5, 26.2, 24.4,
21.7, 19.1 ppm. HRMS (FAB+): calcd. for C16H21NSO4I 450.0236;
found 450.0237.
10-Iodo-6-oxaspiro[4.5]decan-7-one (22): Highly photosensitive
oil. IR (film): ν = 2955 (m), 2923 (m), 2870 (m), 1730 (s), 1626 (m),
˜
1434 (m), 1344 (m), 1251 (m), 1205 (m), 1163 (s), 1062 (m), 1028 (s),
1
5-Iodo-6-pentyltetrahydro-2H-pyran-2-one (20a and 20b): Iodo-
acetic acid (6b) and allylic alcohol 7k were used in the general
procedure for Method B to give a separable mixture of iodolactone
diastereomers trans-20a and cis-20b (54 % yield).
991 (m), 913 (w), 884 (w), 765 (w) cm–1. H NMR (400 MHz, CDCl3):
δ = 4.49 (t, J = 4.4 Hz, 1 H), 2.90 (ddd, J = 18.8, 9.3, 8.1 Hz, 1 H),
2.65 (dddd, J = 18.8, 7.3, 3.2, 0.7 Hz, 1 H), 2.45–2.35 (m, 1 H), 2.34–
2.26 (m, 1 H), 2.13–1.99 (m, 3 H), 1.97–1.77 (m, 4 H), 1.75–1.61 (m,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.2, 94.6, 42.1, 38.4,
32.4, 29.9, 28.4, 25.6, 23.4 ppm. HRMS (DART): calcd. for C9H14IO2
[M + H]+ 281.00385; found 281.00322.
(5R*,6S*)-5-Iodo-6-pentyltetrahydro-2H-pyran-2-one (20a): Vol-
atile colorless oil. IR (film): ν = 2954 (s), 2926 (s), 2857 (m), 1738 (s),
˜
1457 (m), 1415 (w), 1381 (m), 1335 (m), 1246 (m), 1198 (m), 1172
(m), 1142 (m), 1114 (m), 1053 (m), 1020 (m), 942 (w), 912 (w), 884 5-Iodo-1-oxaspiro[5.5]undecan-2-one (23): Highly photosensitive
1
(w), 732 (m) cm–1. H NMR (400 MHz, CDCl3): δ = 4.51 (td, J = 8.4,
3.1 Hz, 1 H), 4.12 (td, J = 8.7, 5.1 Hz, 1 H), 2.76–2.64 (m, 1 H), 2.61–
2.45 (m, 2 H), 2.43–2.29 (m, 1 H), 2.01 (dddd, J = 13.9, 10.6, 5.6,
3.0 Hz, 1 H), 1.75 (dddd, J = 14.3, 10.3, 8.1, 4.8 Hz, 1 H), 1.59–1.50
(m, 1 H), 1.48–1.24 (m, 5 H), 0.90 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.0, 85.0, 34.8, 31.9, 31.4, 30.8, 24.2, 22.9,
22.5, 14.0 ppm. HRMS (DART): calcd. for C10H18IO2 [M + H]+
297.03515; found 297.03546.
oil. IR (film): ν = 2927 (s), 2859 (m), 1716 (s), 1447 (m), 1332 (m),
˜
1274 (m), 1209 (s), 1142 (s), 1097 (m), 1039 (m), 1009 (m), 987 (s),
913 (m), 892 (w), 867 (w), 760 (m), 658 (w), 589 (m), 520 (m), 486
1
(m) cm–1. H NMR (400 MHz, CDCl3): δ = 4.48 (dd, J = 6.0, 3.9 Hz, 1
H), 2.85 (dt, J = 18.1, 7.9 Hz, 1 H), 2.69–2.50 (m, 2 H), 2.42–2.30 (m,
1 H), 2.03–1.87 (m, 2 H), 1.83–1.65 (m, 4 H), 1.64–1.45 (m, 3 H), 1.37–
1.19 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.3, 83.3, 38.6,
35.5, 34.6, 28.81, 28.76, 25.0, 21.9, 21.5 ppm. HRMS (FAB+): calcd.
for C10H16IO2 [M + H]+ 295.0195; found 295.0193.
(5R*,6R*)-5-Iodo-6-pentyltetrahydro-2H-pyran-2-one (20b): Vol-
atile yellow oil. IR (film): ν = 2955 (s), 2926 (s), 2857 (m), 1736 (s),
5-Iodo-1-oxaspiro[5.6]dodecan-2-one (24): Highly photosensitive
˜
1447 (m), 1411 (m), 1378 (m), 1352 (m), 1240 (s), 1200 (m), 1113 oil. IR (film): ν = 2925 (s), 2856 (m), 1732 (s), 1455 (m), 1346 (w),
˜
1
(m), 1045 (s), 921 (w), 762 (w) cm–1. H NMR (400 MHz, CDCl3): δ =
4.49 (q, J = 2.9 Hz, 1 H), 3.45 (ddd, J = 7.5, 5.7, 1.9 Hz, 1 H), 2.90
(ddd, J = 18.7, 10.1, 8.6 Hz, 1 H), 2.68 (ddd, J = 18.8, 5.7, 3.7 Hz, 1
H), 2.41–2.28 (m, 2 H), 1.86–1.71 (m, 1 H), 1.64–1.48 (m, 1 H), 1.47–
1331 (w), 1247 (m), 1200 (w), 1165 (m), 1023 (m), 918 (w), 881 (w),
1
834 (w), 768 (w) cm–1. H NMR (400 MHz, CDCl3): δ = 4.48 (dd, J =
6.5, 4.0 Hz, 1 H), 2.83 (dt, J = 18.4, 8.4 Hz, 1 H), 2.66–2.58 (m, 1 H),
2.51 (dtd, J = 15.2, 7.6, 4.0 Hz, 1 H), 2.38 (dddd, J = 14.9, 8.2, 6.5,
1.24 (m, 6 H), 0.90 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, 4.5 Hz, 1 H), 2.13–1.94 (m, 4 H), 1.83–1.59 (m, 4 H), 1.60–1.42 (m, 4
CDCl3): δ = 169.2, 81.9, 37.7, 31.5, 30.9, 30.6, 28.4, 24.2, 22.5,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.4, 87.6, 41.7, 38.9,
14.0 ppm. HRMS (DART): calcd. for C10H18IO2 [M + H]+ 297.03515; 34.4, 29.3, 29.2, 28.9 (2 C), 22.6, 22.4 ppm. HRMS (DART): calcd. for
found 297.03596.
C11H18IO2 [M + H]+ 309.03515; found 309.03595.
5-Iodo-6-[(S)-1-tosylpyrrolidin-2-yl]tetrahydro-2H-pyran-2-one
(21a and 21b): Iodoacetic acid (6b) and allylic alcohol 7l were used
in the general procedure for Method B to give a separable mixture
of diastereomers trans-21a and cis-21b (71 % yield).
10-Iodo-8-methyl-6-oxaspiro[4.5]decan-7-one (25a and 25b): 2-
Iodopropionic acid (6c) and allylic alcohol 7m were used in the
general procedure for Method B to give a separable mixture of
diastereomers trans-25a and cis-25b (79 % combined yield).
(–)-(5S,6R)-5-Iodo-6-[(S)-1-tosylpyrrolidin-2-yl]tetrahydro-2H-
(8R*,10R*)-10-Iodo-8-methyl-6-oxaspiro[4.5]decan-7-one (25a):
pyran-2-one (21a): Yellow solid; m.p. 127–129 °C. [α]D25 = –42.0 (c = White solid; m.p. 47–48 °C. IR (film): ν = 2958 (m), 2926 (m), 2874
˜
0.59, CHCl3). IR (KBr): ν = 3421 (w), 2956 (w), 2924 (m), 2885 (w), (m), 2853 (m), 1731 (s), 1453 (m), 1378 (m), 1344 (m), 1303 (w), 1237
˜
1744 (s), 1597 (w), 1451 (w), 1343 (m), 1195 (m), 1159 (s), 1091 (m), (m), 1208 (m), 1157 (m), 1053 (m), 1010 (m), 982 (w), 925 (w), 747
1
1051 (m), 988 (w), 817 (w), 666 (s) cm–1. H NMR (400 MHz, CDCl3):
δ = 7.76 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 7.6 Hz, 2 H), 5.11 (dt, J =
3.2, 1.6 Hz, 1 H), 3.77–3.71 (m, 1 H), 3.57 (dd, J = 6.5, 1.6 Hz, 1 H),
(w) cm–1 1H NMR (400 MHz, CDCl3): δ = 4.51 (t, J = 4.0 Hz, 1 H),
.
3.05 (dq, J = 10.8, 7.2 Hz, 1 H), 2.42–2.33 (m, 1 H), 2.14–1.99 (m, 4
H), 1.97–1.78 (m, 4 H), 1.72–1.61 (m, 1 H), 1.36 (d, J = 7.2 Hz, 3
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H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.0, 94.8, 43.7, 39.0, 38.3,
34.0, 33.3, 25.8, 23.4, 17.0 ppm. HRMS (DART): calcd. for C10H16IO2
[M + H]+ 295.01950; found 295.01933.
14.7, 10.2, 1.6 Hz, 1 H), 1.94–1.85 (m, 2 H), 1.83–1.70 (m, 2 H), 1.69–
1.48 (m, 6 H), 1.29 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 173.2, 87.9, 41.8, 39.2, 38.0, 37.1, 32.4, 29.0, 29.0, 23.2,
22.8, 17.1 ppm. HRMS (DART): calcd. for C12H20IO2 [M + H]+
323.05080; found 323.05166.
(8R*,10S*)-10-Iodo-8-methyl-6-oxaspiro[4.5]decan-7-one (25b):
Yellow solid; m.p. 48–49 °C. IR (film): ν = 2962 (m), 2934 (m), 2873
˜
3′-Iodo-3,4,4′,5′-tetrahydro-1H-spiro[naphthalene-2,2′-pyran]-
6′(3′H)-one (28a and 28b): Iodoacetic acid (6b) and allylic alcohol
7p were used in the general procedure for Method B to give a
separable mixture of diastereomers trans-28a and cis-28b (68 %
combined yield).
(m), 1731 (s), 1452 (m), 1434 (m), 1376 (w), 1340 (m), 1238 (m), 1160
(m), 1088 (w), 1047 (w), 1008 (m), 975 (m), 919 (w), 775 (w), 748
1
(w) cm–1. H NMR (400 MHz, CDCl3): δ = 4.54 (dd, J = 10.8, 3.9 Hz,
1 H), 2.75–2.59 (m, 2 H), 2.31–2.16 (m, 2 H), 2.15–2.06 (m, 1 H), 2.04–
1.88 (m, 4 H), 1.77–1.68 (m, 2 H), 1.33 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 173.1, 95.0, 40.0, 39.4, 38.2, 37.2, 29.5,
25.0, 24.5, 17.6 ppm. HRMS (DART): calcd. for C10H16IO2 [M + H]+
295.01950; found 295.01996.
(2R*,3′S*)-3′-Iodo-3,4,4′,5′-tetrahydro-1H-spiro[naphthalene-
2,2′-pyran]-6′(3′H)-one (28a): Yellow oil. IR (film): ν = 3060 (w),
˜
3019 (w), 2924 (s), 2852 (m), 1733 (s), 1583 (w), 1496 (m), 1453 (s),
1412 (m), 1371 (m), 1331 (m), 1281 (s), 1258 (s), 1230 (s), 1201 (s),
1180 (s), 1142 (m), 1113 (m), 1098 (m), 1098 (m), 1053 (s), 1020 (m),
975 (m), 956 (w), 927 (w), 882 (w), 838 (w), 811 (w), 751 (m), 678
5-Iodo-3-methyl-1-oxaspiro[5.5]undecan-2-one (26a and 26b):
2-Iodopropionic acid (6c) and allylic alcohol 7n were used in the
general procedure for Method B to give a separable mixture of
diastereomers trans-26a and cis-26b (81 % combined yield).
(w) cm–1 1H NMR (400 MHz, CDCl3): δ = 7.18–7.04 (m, 4 H), 4.51
.
(dd, J = 6.0, 4.0 Hz, 1 H), 3.25 (d, J = 16.9 Hz, 1 H), 3.16 (d, J =
17.4 Hz, 1 H), 3.12–3.05 (m, 1 H), 2.94 (dt, J = 18.7, 8.2 Hz, 1 H), 2.80
(dt, J = 17.0, 5.8 Hz, 1 H), 2.71 (ddd, J = 18.7, 7.5, 3.8 Hz, 1 H), 2.60
(dtd, J = 15.8, 8.1, 3.9 Hz, 1 H), 2.43 (dddd, J = 15.0, 8.3, 5.8, 3.8 Hz,
1 H), 2.28–2.21 (m, 1 H), 2.17–2.09 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.1, 134.4, 132.5, 129.6, 128.5, 126.6, 126.5, 82.9, 43.3,
32.7, 32.4, 28.85, 28.81, 26.2 ppm. HRMS (DART): calcd. for C14H19I-
NO2 [M + NH4]+ 360.04605; found 360.04514.
(3R*,5R*)-5-Iodo-3-methyl-1-oxaspiro[5.5]undecan-2-one (26a):
White solid; m.p. 58–59 °C. IR (film): ν = 2935 (s), 2862 (m), 1733 (s),
˜
1450 (m), 1376 (w), 1354 (w), 1327 (w), 1277 (w), 1224 (m), 1207
(m), 1144 (m), 1096 (w), 1064 (m), 1022 (w), 1064 (m), 983 (w), 936
(w), 748 (w) cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.56 (t, J = 4.2 Hz,
1 H), 3.08–2.97 (m, 1 H), 2.41 (ddd, J = 15.2, 7.2, 4.4 Hz, 1 H), 2.26
(ddd, J = 15.1, 10.2, 3.8 Hz, 1 H), 2.06–1.98 (m, 1 H), 1.95–1.89 (m,
1 H), 1.78–1.68 (m, 3 H), 1.63–1.44 (m, 4 H), 1.36 (d, J = 7.2 Hz, 3 H),
1.32–1.25 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1, 83.4,
40.4, 37.0, 35.9, 35.8, 34.0, 25.0, 22.2, 21.7, 17.1 ppm. HRMS (DART):
calcd. for C11H18IO2 [M + H]+ 309.03515; found 309.03621.
(2R*,3′R*)-3′-Iodo-3,4,4′,5′-tetrahydro-1H-spiro[naphthalene-
2,2′-pyran]-6′(3′H)-one (28b): White solid; m.p. 86–88 °C (decom-
poses). IR (film): ν = 3060 (w), 3020 (w), 2923 (m), 2850 (m), 1735
˜
(s), 1538 (w), 1495 (m), 1453 (m), 1372 (w), 1348 (m), 1331 (m), 1279
(m), 1243 (m), 1203 (s), 1136 (m), 1099 (m), 1044 (s), 1017 (m), 974
(m), 942 (w), 919 (w), 900 (w), 881 (w), 750 (s) cm–1 1H NMR
.
(3R*,5S*)-5-Iodo-3-methyl-1-oxaspiro[5.5]undecan-2-one (26b):
(400 MHz, CDCl3): δ = 7.19–7.11 (m, 3 H), 7.05–6.99 (m, 1 H), 4.53
(dd, J = 5.2, 3.8 Hz, 1 H), 3.25 (d, J = 16.8 Hz, 1 H), 3.14 (d, J =
16.6 Hz, 1 H), 3.08–2.85 (m, 3 H), 2.72 (dddd, J = 18.7, 7.2, 3.5, 0.7 Hz,
1 H), 2.57 (dddd, J = 15.2, 9.2, 7.2, 3.8 Hz, 1 H), 2.36 (dddd, J = 15.2,
8.0, 5.2, 3.4 Hz, 1 H), 2.31–2.17 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.0, 134.7, 132.1, 129.1, 128.9, 126.9, 126.4, 83.2, 39.0,
36.6, 31.7, 28.8 (2 C), 25.8 ppm. HRMS (DART): calcd. for C14H19INO2
[M + NH4]+ 360.04605; found 360.04657.
Yellow solid; m.p. 75–76 °C. IR (film): ν = 2934 (s), 2863 (m), 1732
˜
(s), 1447 (m), 1374 (w), 1333 (w), 1207 (s), 1150 (m), 1118 (s), 1085
(m), 1032 (m), 970 (m), 926 (w), 871 (w), 695 (w) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 4.32 (dd, J = 12.1, 3.8 Hz, 1 H), 2.67–2.54 (m,
2 H), 2.43–2.32 (m, 1 H), 2.05–1.96 (m, 2 H), 1.84–1.67 (m, 5 H), 1.65–
1.51 (m, 2 H), 1.30 (d, J = 6.8 Hz, 3 H), 1.24–1.16 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 173.1, 84.4, 38.5, 38.0, 37.0, 33.2, 31.5,
25.2, 21.2 (2 C), 17.2 ppm. HRMS (DART): calcd. for C11H18IO2 [M +
H]+ 309.03515; found 309.03647.
5-Iodo-6-methyl-6-phenyltetrahydro-2H-pyran-2-one (29a and
29b): Iodoacetic acid (6b) and allylic alcohol 7q[25] were used in
the general procedure for Method C to give a separable mixture of
trans-29a and cis-29b diastereomers (57 % combined yield).
5-Iodo-3-methyl-1-oxaspiro[5.6]dodecan-2-one (27a and 27b):
2-Iodopropionic acid (6c) and allylic alcohol 7o were used in the
general procedure for Method B to give a separable mixture of
diastereomers trans-27a and cis-27b (80 % combined yield).
(5R*,6S*)-5-Iodo-6-methyl-6-phenyltetrahydro-2H-pyran-2-one
(29a): Photosensitive colorless oil. IR (film): ν = 3446 (br. w), 2983
˜
(m), 2922 (m), 1733 (s), 1612 (m), 1495 (w), 1442 (m), 1377 (w), 1347
(3R*,5R*)-5-Iodo-3-methyl-1-oxaspiro[5.6]dodecan-2-one (27a):
(w), 1329 (w), 1237 (s), 1146 (s), 1076 (m), 1043 (s), 930 (w), 905 (w),
White oil. IR (film): ν = 2925 (s), 2854 (m), 1732 (s), 1458 (m), 1378
˜
1
884 (w), 762 (s), 699 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 7.42–
(w), 1329 (w), 1232 (m), 1148 (m), 1061 (m), 1012 (m), 930 (w) cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.58 (t, J = 4.8 Hz, 1 H), 3.06–2.96
(m, 1 H), 2.45 (ddd, J = 15.1, 7.5, 5.0 Hz, 1 H), 2.21 (ddd, J = 15.1,
9.9, 4.0 Hz, 1 H), 2.08–1.93 (m, 4 H), 1.79–1.40 (m, 8 H), 1.35 (d, J =
7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.3, 87.9, 43.3,
39.1, 37.6, 35.3, 34.1, 29.5, 29.1, 22.8, 22.4, 17.1 ppm. HRMS (DART):
calcd. for C12H20IO2 [M + H]+ 323.05080; found 323.05152.
7.28 (m, 5 H), 4.94 (ddt, J = 3.4, 0.6 Hz, 1 H), 2.94 (dddd, J = 19.0,
10.4, 8.2, 0.4 Hz, 1 H), 2.53 (dddd, J = 19.1, 7.2, 2.1, 0.8 Hz, 1 H), 2.07
(dddd, J = 15.0, 8.2, 3.8, 2.0 Hz, 1 H), 1.95 (dddd, J = 15.0, 10.4, 7.2,
3.4 Hz, 1 H), 1.82 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.7,
141.3, 129.3 (2 C), 128.2, 124.5 (2 C), 86.7, 35.3, 34.2, 28.5, 27.9 ppm.
HRMS (DART): calcd. for C12H14IO2 [M + H]+ 317.00385; found
317.00470.
(3R*,5S*)-5-Iodo-3-methyl-1-oxaspiro[5.6]dodecan-2-one (27b):
(5R*,6R*)-5-Iodo-6-methyl-6-phenyltetrahydro-2H-pyran-2-one
Yellow oil. IR (film): ν = 2927 (s), 2857 (m), 1733 (s), 1458 (m), 1377
(29b): Photosensitive clear oil. IR (film): ν = 3059 (w), 2989 (m), 2926
(m), 2854 (m), 1741 (s), 1600 (w), 1494 (m), 1445 (s), 1409 (w), 2377
˜
˜
(w), 1337 (w), 1224 (m), 1160 (m), 1106 (w), 1065 (w), 1020 (m),
1006 (m), 952 (w), 936 (w), 905 (w), 756 (w) cm–1. 1H NMR (400 MHz, (m), 1345 (m), 1328 (m), 1252 (s), 1202 (s), 1162 (s), 1142 (m), 1097
CDCl3): δ = 4.32 (dd, J = 12.3, 3.8 Hz, 1 H), 2.65–2.53 (m, 2 H), 2.39–
2.29 (m, 1 H), 2.23 (ddd, J = 15.1, 9.9, 1.9 Hz, 1 H), 2.16 (ddd, J =
(m), 1060 (s), 1029 (w), 992 (m), 921 (m), 885 (w), 803 (w), 766 (m),
701 (m), 681 (w) cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.42–7.28 (m,
Eur. J. Org. Chem. 2016, 1739–1750
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5 H), 4.75 (t, J = 3.6 Hz, 1 H), 3.02 (dddd, J = 18.9, 9.6, 8.3, 0.4 Hz, 1 (m, 5 H), 7.10 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 5.05 (s, 2
H), 2.77 (dddd, J = 18.9, 7.4, 2.6, 0.7 Hz, 1 H), 2.60 (dddd, J = 15.1,
9.6, 7.4, 3.7 Hz, 1 H), 2.38 (dddd, J = 15.0, 8.3, 4.6, 2.6 Hz, 1 H), 1.86
(s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 168.9, 144.9, 128.4 (2
C), 128.0 (2 C), 124.3, 86.1, 34.5, 28.6, 28.5, 27.7 ppm. HRMS (DART):
calcd. for C12H14IO2 [M + H]+ 317.00385; found 317.00447.
H), 4.39 (dd, J = 11.9, 2.9 Hz, 1 H), 4.05 (dd, J = 11.9, 6.4 Hz, 1 H),
3.05 (s, 3 H), 2.97 (dt, J = 6.4, 2.2 Hz, 1 H), 2.91 (td, J = 6.0, 2.1 Hz,
1 H), 2.77 (ddd, J = 14.2, 8.3, 6.0 Hz, 1 H), 2.67 (dt, J = 14.0, 8.0 Hz,
1 H), 1.96–1.77 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.4,
137.2, 133.1, 129.4 (2 C), 128.7 (2 C), 128.1, 127.6 (2 C), 115.1 (2 C),
70.2, 69.9, 56.1, 55.3, 38.0, 33.4, 31.2 ppm. HRMS (DART): calcd. for
C
19H26NO5S [M + NH4]+ 380.15317; found 380.15308.
4a-Iodooctahydrocyclohepta[b]pyran-2(3H)-one (30): Iodoacetic
acid (6b) and allylic alcohol 7s were used in the general procedure
for Method A to give compound 30 (30 % yield, single diastereo-
(–)-(S)-5-[4-(Benzyloxy)phenyl]pent-1-en-3-ol (38): To a solution
of 37 (0.137 g, 0.378 mmol) in THF (1.5 mL) was added NaI (0.113 g,
0.756 mmol), and the mixture was heated at reflux for 2 h. The
reaction was cooled to room temp., and the THF was removed by
evaporation. The crude residue was partitioned between water and
ethyl acetate. The organic phase was dried with Na2SO4, and the
solvents were evaporated. The residue was dissolved in MeOH
(1.5 mL), and then zinc dust (0.124 g, 1.890 mmol) and iodine
(0.010 g, 0.038 mmol) were added. The resulting mixture was
heated at reflux for 1 h and then cooled to room temperature. The
mixture was filtered through Celite, and the filter cake was washed
with ethyl acetate. The solvent was removed by evaporation, and
the crude product was purified by flash chromatography (hexane/
ethyl acetate, 9:1) to give 38 (0.063 g, 62 % yield) as a white solid;
mer) as a yellow solid; m.p. 68 °C. IR (film): ν = 3439 (w), 3324 (w),
˜
2925 (s), 2859 (m), 1720 (s), 1447 (m), 1352 (m), 1342 (m), 1250 (m),
1204 (s), 1148 (w), 1090 (w), 1044 (s), 1010 (s), 918 (m), 873 (m), 829
(s), 770 (m), 683 (m), 591 (s), 476 (s), 456 (m) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 3.03–2.93 (m, 2 H), 2.71 (ddd, J = 18.9, 7.6,
1.7 Hz, 1 H), 2.41–2.28 (m, 2 H), 2.10–1.43 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.4, 88.1, 60.2, 42.5, 40.9, 35.5, 30.2, 25.8,
25.4, 21.8 ppm. HRMS (DART): calcd. for C10H16IO2 [M + H]+
295.01950; found 295.01956.
6-Hydroxy-1-oxaspiro[4.6]undecan-2-one (31a and 31b): Yellow
solid (27 % yield, mixture of diastereomers); m.p. 65 °C. IR (film): ν =
˜
3398 (s), 3936 (s), 2856 (m), 1724 (s), 1457 (w), 1407 (w), 1314 (s),
1271 (m), 1251 (m), 1176 (m), 1160 (m), 1035 (m), 1001 (m), 975
m.p. 53–54 °C. [α]D25 = –3.8 (c = 0.54, CHCl3). IR (film): ν = 3298 (br.
˜
(m), 932 (w), 874 (m), 805 (w), 680 (w), 566 (m), 534 (m), 468 (w), m), 3062 (w), 3031 (w), 2925 (w), 2892 (w), 2858 (w), 1611 (m), 1580
439 (w) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.87 (dd, J = 9.9, 2.8 Hz,
1 H, 6-H), 3.55 (dd, J = 9.5, 2.4 Hz, 1 H, 6*-H), 2.78–2.32 (m, 6 H,
3ab-H, 3ab*-H, 4a-H, 4a*-H), 2.10 (br. s, 2 H, OH, OH*), 1.99–1.36 (m,
(w), 1511 (s), 1451 (m), 1383 (m), 1312 (w), 1296 (w), 1255 (s), 1241
(s), 1174 (m), 1118 (w), 1098 (w), 1043 (s), 1014 (s), 984 (s), 916 (s),
857 (w), 821 (m), 785 (w), 734 (s), 694 (s), 636 (w), 611 (m), 560 (m),
22 H, 4b-H, 4b*-H, 7-H, 7*-H, 8-H, 8*-H, 9-H, 9*-H, 10-H, 10*-H, 11- 512 (m) cm–1 1H NMR (400 MHz, CDCl3): δ = 7.46–7.28 (m, 5 H),
.
H, 11*-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.7 (C-2), 177.5
(C-2*), 92.3 (C-5), 90.5 (C-5*), 77.7 (C-6), 77.2 (C-6*), 37.2 (C-11), 36.1 10.4, 6.1 Hz, 1 H), 5.24 (dt, J = 17.2, 1.4 Hz, 1 H), 5.13 (dt, J = 10.4,
(C-11*), 31.5 (C9), 31.4 (C-8), 31.3 (C-4), 30.0 (C-3), 29.1 (C-3*), 26.9 1.3 Hz, 1 H), 5.04 (s, 2 H), 4.11 (qt, J = 6.2, 1.1 Hz, 1 H), 2.75–2.57
7.12 (d, J = 8.4 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 5.90 (ddd, J = 17.2,
(C-9*), 26.8 (C-8*), 26.3 (C-4*), 23.3 (C-10), 22.8 (C-7), 20.9 (C-10*), (m, 2 H), 1.89–1.74 (m, 2 H, 4-H), 1.56 (br. s, 1 H) ppm. 13C NMR
20.5 (C-7*) ppm. HRMS (DART): calcd. for C10H17O3 [M + H]+
185.11777; found 185.11770.
(100 MHz, CDCl3): δ = 157.2, 141.2, 137.3, 134.3, 129.5 (2 C), 128.7
(2 C), 128.0, 127.6 (2 C), 115.0, 114.9 (2 C), 72.6, 70.2, 38.8, 30.9 ppm.
HRMS (DART): calcd. for C18H24NO2 [M + NH4]+ 286.18070; found
286.18077.
8a-Iodooctahydro-3H-isochromen-3-one (32): Iodoacetic acid 6b
and allylic alcohol 7t were used in the general procedure for
Method A to give 32 (47 % yield, single diastereomer) as a yellow
(–)-(R)-6-[4-(Benzyloxy)phenethyl]tetrahydro-2H-pyran-2-one
[(S)-33a]: By following the general procedure for Method A of the
iodolactonization sequence, 38 (0.062 g, 0.231 mmol) and iodoace-
tic acid (6b, 86 mg, 0.462 mmol) in 1,2-DCE (1.5 mL) were treated
with DLP (four additions of 0.018 g, 0.046 mmol). When the iodolac-
tonization step was complete (monitored by TLC analysis), the sol-
vent was removed under reduced pressure, and the residue was
dissolved in benzene (3 mL). Then, azobis(isobutyronitrile) (AIBN,
0.005 g, 0.057 mmol) and tributyltin hydride (0.155 mL, 0.577 mmol)
were added. The mixture was degassed with argon for 5 min and
then heated at reflux for 1 h. Then, the reaction was cooled to room
temperature, and the solvent removed by evaporation. The crude
residue was purified by flash chromatography (hexane/ethyl acet-
ate/acetic acid, 94.5:5:0.5 to 84.5:15:0.5) to give of (S)-33a (49 mg,
70 % yield) as a white solid; m.p. 79–80 °C. [α]D25 = –41.8 (c = 0.39,
oil . IR (film): ν = 3439 (w), 3033 (s), 2987 (w), 2940 (m), 2861 (w),
˜
1733 (s), 1461 (w), 1445 (w), 1374 (m), 1342 (m), 1248 (s), 1236 (s),
1211 (w), 1192 (w), 1046 (m), 919 (w), 850 (w) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 4.62 (d, J = 12.5 Hz, 1 H), 4.26 (d, J = 12.5 Hz,
1 H), 2.65 (dd, J = 18.8, 6.0 Hz, 1 H), 2.29 (dd, J = 18.4, 12.0 Hz, 1
H), 2.24–2.19 (m, 1 H), 2.02–1.93 (m, 1 H), 1.86–1.76 (m, 2 H), 1.61–
1.53 (m, 1 H), 1.42–1.13 (m, 3 H), 0.36 (dddd, J = 12.0, 10.8, 5.8,
3.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.5, 82.0, 58.9,
42.7, 38.1, 37.6, 30.1, 24.5, 22.8 ppm. HRMS (DART): calcd. for
C9H14IO2 [M + H]+ 281.00385; found 281.00411.
(–)-{(2S,3S)-3-[4-(Benzyloxy)phenethyl]oxiran-2-yl}methyl Meth-
anesulfonate (37): To a solution of of 36[23] (0.42 g, 1.492 mmol)
in dry CH2Cl2 (15 mL) at 0 °C were added triethylamine (0.416 mL,
2.984 mmol) and methanesulfonyl chloride (0.172 mL, 2.238 mmol), CHCl3). IR (film): ν = 3026 (w), 2953 (w), 2926 (w), 2857 (w), 1724
˜
and the resulting mixture was stirred at 0 °C for 2 h. The reaction
was quenched with water, and the mixture was extracted with
CH2Cl2. The organic layer was dried with Na2SO4, concentrated, and
(s), 1608 (w), 1579 (w), 1510 (m), 1453 (m), 1416 (w), 1382 (m), 1363
(w), 1329 (w), 1298 (w), 1230 (s), 1194 (m), 1173 (m), 1152 (m), 1104
(w), 1052 (s), 1016 (s), 983 (m), 929 (m), 858 (w), 831 (m), 814 (m),
purified by flash chromatography (hexane/ethyl acetate, 4:1) to give 783 (w), 745 (s), 698 (m), 640 (w), 613 (w), 546 (w), 528 (w), 514
37 (0.525 g, 97 % yield) as a white solid; m.p. 77–78 °C. [α]D25 = –16.6 (w) cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.48–7.29 (m, 5 H), 7.11 (d,
(c = 0.53, CHCl3). IR (film): ν = 3028 (w), 2982 (w), 2983 (w), 2855
(w), 1610 (m), 1582 (w), 1511 (s), 1476 (w), 1452 (m), 1385 (w), 1344
(s), 1296 (w), 1253 (s), 1238 (s), 1165 (s), 1115 (w), 1088 (w), 1040
J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 5.04 (s, 2 H), 4.25 (dddd,
J = 11.1, 8.3, 4.3, 2.8 Hz, 1 H), 2.80 (ddd, J = 14.5, 9.4, 5.5 Hz, 1 H),
2.69 (ddd, J = 13.9, 9.1, 7.2 Hz, 1 H), 2.63–2.53 (m, 1 H), 2.51–2.39
(m, 1 H), 2.06–1.95 (m, 1 H), 1.94–1.78 (m, 4 H), 1.63–1.51 (m, 1
˜
(m), 1011 (m), 980 (s), 965 (s), 925 (m), 884 (m), 830 (s), 806 (s), 781
1
(m), 736 (s), 695 (m) cm–1. H NMR (400 MHz, CDCl3): δ = 7.44–7.29 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0, 157.3, 137.3, 133.5,
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129.6 (2 C), 128.7 (2 C), 128.0, 127.6 (2 C), 115.0 (2 C), 79.5, 70.2,
CDCl3): δ = 157.2, 156.2, 136.0, 134.0, 130.1 (2 C), 127.8 (2 C), 115.9
37.8, 30.3, 29.6, 28.0, 18.6 ppm. HRMS (DART): calcd. for C20H23O3 (2 C), 115.6 (2 C), 79.9, 77.7, 39.5, 34.6, 32.1, 31.5, 24.8 ppm. HRMS
[M + H]+ 311.16472; found 311.16483.
(EI): calcd. for C19H22O3 [M]+ 298.1569; found 298.1553.
(–)-(2R,6S)-2-[4-(Benzyloxy)phenethyl]-6-[4-(benzyloxy)phen-
yl]tetrahydro-2H-pyran (39): To a solution of p-bromobenzyloxy-
benzene (34a,[24] 0.083 g, 0.315 mmol) in dry THF (1 mL) at –78 °C
Acknowledgments
We wish to thank Dirección General de Apoyo al Personal Aca-
démico - Universidad Nacional Autónoma de México (DGAPA-
UNAM) (project number IN202915) and Consejo Nacional de
Ciencia y Tecnología (CONACyT) (project number 219925) for
the financial support. D. F. L.-R. and M. M.-C. thank the CONACyT
for the graduate scholarship (grant numbers 255245 and
240054, respectively). We also thank Angeles Peña-González,
Elizabeth Huerta-Salazar, Beatriz Quiroz, Luis Velasco, and Fran-
cisco J. Flores for the technical support (NMR and MS) as well
as Dr. Fernando Sartillo-Piscil (BUAP) for the helpful, friendly
discussions and corrections.
under argon was added n-butyllithium (2.5
M solution in THF,
0.118 mL, 0.295 mmol). After the resulting mixture was stirring at
–78 °C for 1 h, a solution of lactone (S)-33a (0.061 g, 0.197 mmol)
in of dry THF (1 mL) was transferred by cannula into the reaction
flask, and the reaction mixture was stirred at –78 °C until there was
complete consumption of the starting material (monitored by TLC
analysis). The reaction was quenched with a saturated aqueous
NH4Cl solution, and the mixture was extracted with CH2Cl2. The
organic layer was dried with Na2SO4, filtered, and concentrated. The
crude lactol was used directly in the reduction step without further
purification. To a solution of the crude lactol in dry CH2Cl2 (2 mL)
at –78 °C was added triethylsilane (0.126 mL, 0.788 mmol) followed
by the dropwise addition of BF3·OEt2 (0.097 mL, 0.788 mmol). The
temperature was increased to –40 °C, and the reaction was stirred
for 1.5 h and then quenched with water. The mixture was neutral-
ized with triethylamine and then extracted with CH2Cl2. The organic
extract was dried with Na2SO4, filtered, and concentrated under
reduced pressure to give the crude residue. Purification by flash
chromatography (hexane/ethyl acetate, 99:1 to 95:5) gave 39
(0.041 g, 44 % yield) as a white solid along with the recovered start-
ing material (5.4 mg, 48 % yield based on recovered starting mate-
Keywords: Synthetic methods · Lactones · Radical
reactions · Carboxylic acids · Allylic compounds
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rial), m.p. 68–69 °C. [α]D25 = –44.7 (c = 1.02, CHCl3). IR (KBr): ν = 3061
˜
(w), 3031 (w), 2927 (m), 2857 (m), 1736 (w), 1610 (m), 1583 (m),
1510 (s), 1452 (m), 1381 (m), 1349 (w), 1312 (m), 1296 (m), 1243 (s),
1207 (m), 1173 (m), 1140 (w), 1113 (w), 1080 (m), 1039 (s), 1025 (s),
994 (m), 945 (w), 919 (w), 904 (w), 834 (m), 809 (m), 783 (m), 729
(s), 693 (s), 673 (w), 614 (w), 574 (w), 539 (m), 461 (w) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.46–7.28 (m, 12 H), 7.11 (d, J = 8.6 Hz, 2 H),
6.95 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 5.06 (s, 2 H), 5.03
(s, 2 H), 4.29 (dd, J = 11.1, 2.4 Hz, 1 H), 3.44 (dddd, J = 11.1, 7.9, 4.7,
2.0 Hz, 1 H), 2.77–263 (m, 2 H), 1.96–1.86 (m, 2 H), 1.82 (dd, J =
14.8, 2.7 Hz, 1 H), 1.72 (dddd, J = 18.1, 8.8, 4.4, 2.5 Hz, 1 H), 1.66–
1.57 (m, 2 H), 1.49 (tdd, J = 12.9, 11.0, 3.7 Hz, 1 H), 1.37–1.29 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.1, 157.0, 137.4, 137.3,
136.3, 135.0, 129.5 (2 C), 128.7 (4 C), 128.0 (2 C), 127.62 (2 C), 127.58
(2 C), 127.2 (2 C), 114.8 (2 C), 114.7 (2 C), 79.1, 77.3, 70.19, 70.16,
38.4, 33.5, 31.4, 30.9, 24.2 ppm. HRMS (DART): calcd. for C33H35O3
[M + H]+ 479.25862; found 479.25884.
(–)-De-O-methylcentrolobine (35): To a solution of 39 (0.041 g,
0.085 mmol) in MeOH (5 mL) were added Pd(OH)2 (20 wt-% over
charcoal, 0.008 g). The reaction flask was charged with H2 and then
stirred vigorously for 24 h. The reaction was filtered through Celite,
and the filter cake was washed with MeOH and acetone. The solvent
was removed by evaporation, and the crude product was purified
by flash chromatography (hexanes/ethyl acetate, 7:3) to give 35
(0.018 g, 70 % yield) as a white solid; m.p. 170 °C. [α]D25 = –67.6 (c =
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1.07, MeOH). IR (KBr): ν = 3360 (br. s), 3065 (w), 3024 (w), 2974 (m),
˜
2919 (m), 2842 (m), 1887 (w), 1701 (w), 1653 (w), 1613 (m), 1600
(m), 1512 (s), 1441 (m), 1367 (m), 1311 (w), 1292 (w), 1267 (m), 1228
(s), 1173 (m), 1152 (w), 1121 (w), 1087 (m), 1022 (m), 982 (w), 956
(w), 940 (w), 919 (w), 900 (w), 863 (w), 825 (s), 785 (w), 752 (w), 617
(w), 574 (w), 548 (w), 536 (w), 523 (w), 508 (w), 444 (w) cm–1 1H
.
NMR (400 MHz, [D6]acetone): δ = 8.19 (s, 1 H), 8.04 (s, 1 H), 7.23–
7.18 (m, 2 H), 7.05–6.98 (m, 2 H), 6.81–6.77 (m, 2 H), 6.75–6.71 (m,
2 H), 4.26 (dd, J = 11.2, 2.1 Hz, 1 H), 3.42 (dddd, J = 9.8, 7.9, 4.5,
1.8 Hz, 1 H), 2.71–2.56 (m, 2 H), 1.92–1.85 (m, 1 H), 1.82–1.59 (m, 5
H), 1.47–1.36 (m, 1 H), 1.32–1.25 (m, 1 H) ppm. 13C NMR (100 MHz,
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Received: January 14, 2016
Published Online: March 2, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim